Preparation of gamma-pyrones

ABSTRACT

2-METHYL-3-HYDROXY-4H-pyran-4-one is prepared by contacting 1(2-furyl)-1-ethanol in aqueous solution with two equivalents of a halogen oxidant at room temperature and then heating until the hydrolysis of the formed 4-halo-dihydropyran intermediate is substantially complete. Other valuable related gamma-pyrones are prepared in analogous manner from appropriate alcohols.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of co-pending application,Ser. No. 710,901 filed Aug. 2, 1976 now abandoned.

BACKGROUND OF THE INVENTION

Maltol is a naturally occurring substance found in the bark of younglarch trees, pine needles and chicory. Early commercial production wasfrom the destructive distillation of wood. Synthesis of maltol from3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was reported by Spielman andFreifelder in J. Am. Chem. Soc., 69, 2908 (1947). Schenck and Spielman,J. Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkalinehydrolysis of streptomycin salts. Chawla and McGonigal, J. Org. Chem.,39, 3281 (1974) and Lichtenthaler and Heidel, Angew. Chem., 81, 998(1969), reported the synthesis of maltol from protected carbohydratederivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 1363(1976), described a five step synthesis of maltol starting with methylfurfuryl alcohol.

The isolation of 6 -methyl-2-ethyl-3-hydroxy-4H-pyran-4-one as one ofthe characteristic sweet-aroma components in refinery final molasses wasreported by Hiroshi Ito in Agr. Biol. Chem., 40 (5), 827- 832 (1976).This compound was previously synthesized by the process described inU.S. Pat. No. 3,468,915.

Syntheses of gamma-pyrones such as pyromeconic acid, maltol, ethylmaltol and other 2-substituted-3-hydroxy-gamma-pyrones are described inU.S. Pat. Nos. 3,130,204; 3,133,089; 3,140,239; 3,159,652; 3,365,469;3,376,317; 3,468,915; 3,440,183; and 3,446,629.

Maltol and ethyl maltol enhance the flavor and aroma of a variety offood products. In addition, these materials are used as ingredients inperfumes and essences. The 2-alkenylpyromeconic acids reported in U.S.Pat. No. 3,644,635 and the 2-arylmethylpyromeconic acids described inU.S. Pat. No. 3,365,469 inhibit the growth of bacteri and fungi and areuseful as flavor and aroma enhancers in foods and beverages and aromaenhancers in perfumes.

SUMMARY OF THE INVENTION

This invention is concerned with a process for preparing a gamma-pyroneof the formula ##STR1## wherein R is hydrogen, alkyl of 1 to 4 carbonatoms, phenyl or benzyl; and R'" is hydrogen or alkyl of 1 to 4 carbonatoms which comprises contacting a furfuryl alcohol of the formula##STR2## with two equivalents of a halogen oxidant and heating until thehydrolysis of the formed 4-halo-dihydropyran is substantially complete.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with a novel and facile synthesis ofmaltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds.

A furfuryl alcohol in aqueous medium is treated with two equivalents ofoxidant and the reaction mixture then heated to hydrolyze the finalformed intermediate. The one pot process is represented as follows:##STR3## wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl orbenzyl; R'" is hydrogen or alkyl of 1 to 4 carbon atoms; and XY is Cl₂,Br₂, BrCl, HOCl, HOBr or mixtures thereof.

The reaction pathway is shown in the following scheme: ##STR4##

Lefebvre and co-workers in J. Med. Chem., 16, 1084 (1973) demonstratedthat furfuryl alcohols could be directly converted to6-hydroxy-2H-pyran-3(6H)-ones when a peracid oxidant such as peraceticacid or m-chloroperbenzoic acid is employed. The first step of theLefebvre work uses a peracid in an organic solvent and probably leads toa 6-acetoxy or 6-m-chlorobenzoyloxy pyran derivative which is hydrolyzedto the 6-hydroxy compound during the aqueous work-up. Water is not usedin the first step of the reaction, and would in fact be deleterious. Inany case, the process of Lefebvre and co-workers cannot lead directly tothe conversion of a furfuryl alcohol to a gamma-pyrone.

Critical to the process of the present invention is the use of anaqueous solution of a halogen oxidant. A furfuryl alcohol can be cleanlyoxidized to a 6-hydroxy-2H-pyran-3(6H)-one using one equivalent of ahalogen oxidant in water or water/organic co-solvent. It is surprisingand an unexpected finding that 6-hydroxy-2H-pyran-3(6H)-ones can beconverted to gamma-pyrones. A 6-hydroxy-2H-pyran-3(6 H)-one may beregarded as a hemi-acetal of an aldehyde and as such might be expectedto undergo numerous undesired side reactions such as over oxidation,aldol-type condensations, etc. Employing two equivalents of halogenoxidant in water or water and organic co-solvent, the reaction proceedssmoothly from a furfuryl alcohol to a gamma-pyrone. This novel one potprocess offers the advantages of employing low cost Cl₂, Br₂, BrCl,HOCl, HOBr or mixtures thereof as the halogen oxidant. Isolation of thedesired gamma-pyrone is greatly simplified since solvent, oxidant andby-product mineral acid are all volatile and can be removed in vacuo toafford crude gamma-pyrone directly in high yield by simpleconcentration.

The one pot process is operated by dissolving a furfuryl alcohol inwater or water and a co-solvent. The co-solvent can be water miscible orwater immiscible and can be selected from a wide range of solvents suchas C₁ to C₄ alkanols or diols; C₂ to C₁₀ ethers; low molecular weightnitriles; and low molecular weight esters. The preferred co-solvents areC₁ to C₄ alkanols and C₂ to C₁₀ ethers, with methanol the choice ofsolvents because of cost. The solution is kept at a temperature of -50°to 50° C., preferably -10° to 10° C. To this solution is charged adesired furfuryl alcohol while simultaneously adding a halogen oxidant(two equivalents) to the reaction mixture. The temperature of thereaction mixture is maintained at -10° to 10° C. during halogenaddition. If a low-boiling co-solvent is employed, it is removed bydistillation after all additions are complete. The reaction mixture isthen heated to a temperature at which the hydrolysis proceeds at areasonable rate (70° to 160° C.). The generally employed reactiontemperature is 100°-110° C. The heating is continued until thehydrolysis of the formed 4-halo-dihydropyran intermediate issubstantially complete (1 to 2 hours). The acid necessary to catalyzethis final hydrolysis is generated in situ by loss of acid from theintermediates formed during the course of the reaction. Additional acidcan be added if desired.

The halogen oxidant can be chlorine, bromine, bromine chloride,hypochlorous or hypobromous acid or mixtures thereof. Bromine chlorideis a commercially available gas. It can be prepared in situ by theaddition of chlorine to a solution of sodium or potassium bromide or bythe addition of bromine to a solution of sodium or potassium chloride.Hypochlorous and hypobromous acid can be conveniently generated in situby the addition of aqueous acid (HCl, H₂ SO₄, HBr, etc.) to a solutionof the alkali or alkali earth metal hypohalite, e.g., NaOCl, KOCl orCa(OCl)₂. The preferred halogen oxidants, based on cost factors, arechlorine and bromine-chloride prepared in situ.

If desired, a 6-hydroxy-2H-pyran-3(6H)-one can be prepared by contactingthe appropriate furfuryl alcohol with one equivalent of a halogenoxidant. The isolated product is readily converted to the desiredgamma-pyrone by contacting it with an additional equivalent of a halogenoxidant and hydrolyzing the formed4-halogeno-6-hydroxy-2H-pyran-3(6H)-one as previously described.

Alternatively, a furfuryl alcohol in aqueous solution with an optionalcosolvent is contacted at -10° to 10° C. with two equivalents of ahalogen oxidant. After stirring at room temperature for about 30minutes, the pH of the reaction mixture is adjusted to about 2 with astrong base and the reaction mixture is extracted with a solvent such asethyl acetate. Removal of the solvent yields the4-halogeno-6-hydroxy-2H-pyran-3(6H)-one which may be hydrolyzed to thedesired gamma-pyrone. The 4-halo-dihydropyran may be dehydrated byheating under vacuum to yield the 6,6'-oxybis[4-halogeno-2H-pyran-3(6H)-one]. This dimer yields the desiredgamma-pyrone on hydrolysis, with added acid if desired.

The subject gamma-pyrones can also be prepared by treatment with ahalogen oxidant with a compound of the formula ##STR5## wherein R ishydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R' is alkylof 1 to 4 carbon atoms and ##STR6## wherein R" is methyl, ethyl orphenyl; and R'" is hydrogen or alkyl of 1 to 4 carbon atoms.

A 6-alkoxy-2H-pyran-3(6H)-one may be prepared by the method described inTetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol isanodically alkoxylated to the2-(1-hydroxyalkyl)-2,5-dialkoxy-dihydrofuran. Treatment with a stongorganic acid produces the desired 6-alkoxy compound. A 6-acyl compoundmay be prepared by conventional treatment of the 6-hydroxy compound withthe appropriate anhydride in the presence of pyridine.

A 6-acyl or 6-alkoxy-2 H-pyran-3(6H)-one is dissolved in areaction-inert solvent selected from the group consisting of aceticacid, formic acid, trifluoroacetic acid, halogenated solvents, ethers,C₁ to C₄ alkanols or diols, low molecular weight ketones, nitriles,esters and amides. The preferred solvents are acetic acid, formic acidor methanol. An equivalent of a halogen oxidant such as chlorine,bromine, bromine-chloride, hypochlorous acid or hypobromous acid isadded at room temperature and the reaction mixture is heated to 70°-160°C., generally 100°-110° C., until the conversion to the desiredgamma-pyrone is substantially complete (approximately 1- 3 hours). Thegamma-pyrone may be obtained from the cooled, neutralized reactionmixture on standing or by extracting the reaction mixture with a solventsuch as chloroform which yields the gamma-pyrone on concentration.

With organic acids and other protic solvents such as formic acid, aceticacid, other organic acids and alkanols that have not been vigorouslydried, no additional water is added in the above described reaction.However, with nonprotic solvents, water is necessary and is added forthe conversion of the formed 4-halogeno-6-substituted-2H-pyran-3(6H)-oneto the pyrone. When a lowboiling solvent is employed in the reaction, itis removed by distillation just before the reaction mixture is heated to100°-110° C. for the hydrolytic conversion of the formed4halo-dihydropyran to the gamma-pyrone.

If desired, the 4-halo-dihydropyran may be prepared and isolated byconducting the halogenation at about -20° to 20° C., preferably 5°-10°C., in the presence of an organic base such as triethylamine. Afterabout 30 minutes the reaction mixture is allowed to warm to roomtemperature, filtered to remove triethylamine hydrochloride and thesolvent removed under vacuum to yield the 4-halo-dihydropyran. Thiscompound is readily hydrolyzed to the gamma-pyrone by heating for aboutan hour in aqueous solution, with added acid if desired, at 70°-160° C.,preferably 100°-110° C.

This process wherein the 6-acyl or6-alkoxy-2H-pyran-3(6H)-one iscontacted in an organic solvent with an equivalent of a halogen oxidantand the intermediate 4-halo-dihydropyran heated until the conversion tothe desired gamma-pyrone is substantially complete differs from themulti-step process described by Shono and Matsumura in TetrahedronLetters 17, 1363 (1976) wherein the 6-alkoxy-2H-pyran-3(6H)-one istreated with a methanolic solution of hydrogen peroxide with sodiumhydroxide solution to yield an epoxy ketone. The isolated epoxy ketoneis then refluxed in water with Dowex 50 ion exchange resin to yield thedesired gamma-pyrone.

In the following examples where spectral data are given, NMR chemicalshift data are reported by conventional literature symbolism and allshifts are expressed as δ units from tetramethyl silane:

s = singlet

d = doublet

t = triplet

q = quartet

m = multiplit

br = broad

EXAMPLE 1

In a 3-neck round bottom flask equipped with a magnetic stirring bar, agas inlet tube, a thermometer and an addition funnel was added 20 ml oftetrahydrofuran and 50 ml of water. The solution was cooled to atemperature of 0° to 20° C. The addition funnel was charged with asolution of 1(2-furyl)-1-ethanol (0.089 moles) in 20 ml oftetrahydrofuran and this was added dropwise to the stirred reactionflask while chlorine (0.30 mole) was added via the gas inlet tube. Therate of addition was such that all the alcohol was added in the first1.3-1.5 equivalents of chlorine (approximately 30 minutes) whilemaintaining the reaction temperature below 10° C. The reaction mixturewas heated to reflux and the tetrahydrofuran removed by distillation.When the reaction mixture reached a temperature of about 105° C., acondenser was added and the refluxing continued for about 2 hours. Thereaction mixture was then filtered hot, cooled, the pH adjusted to 2.2and the reaction mixture was cooled to 5° C. Crystallization andfiltration yielded 3.43 grams of crude 3-hydroxy-2-methyl-γ -pyrone(maltol). The aqueous filtrate was extracted with CHCl₃ to obtain asecond crop of 2.58 g of maltol. Distillation of the combined solids andrecrystallization from methanol gave 5.5 g (49%) of pure white maltol,m.p. 159.5°-160.5° C.

EXAMPLE 2

The method of Example 1 was repeated under varying conditions as shownin Table I with furfuryl alcohols of the formula ##STR7##

                  Table 1.                                                        ______________________________________                                        One Pot Process using chlorine as the oxidant.                                                     Temp.     Temp.                                                               (° C) of                                                                         (° C) of                                                                       Yield                                  R      Cosolvent     oxidation hydrolysis                                                                            (%)                                    ______________________________________                                        CH.sub.3                                                                             methanol      10        100     45                                     CH.sub.3                                                                             methanol      5         110     56                                     CH.sub.3                                                                             methanol      -5        104     60                                     CH.sub.3                                                                             methanol      -10       104     77                                     CH.sub.3                                                                             methanol      -20       106     62-67                                  CH.sub.3                                                                             THF           10        105     49                                     CH.sub.3                                                                             acetone       -5        110     36                                     CH.sub.3                                                                             CH.sub.3 CN   -5        110     29                                     CH.sub.3                                                                             Et OAc        0         110     26                                     CH.sub.3                                                                             none          10        110     17-30                                  CH.sub.3                                                                             benzene       10        110     26                                     CH.sub.3                                                                             methyl isobutyl                                                                             5         110     44                                            ketone                                                                 CH.sub.3                                                                             isopropyl alcohol                                                                           0         110     49                                     CH.sub.2 CH.sub.3                                                                    methanol      5         110     49                                     CH.sub.2 CH.sub.3                                                                    methanol      -10       110     58                                     CH.sub.2 CH.sub.3                                                                    THF           10°                                                                              110     47                                     H      methanol      -10°                                                                             110     57                                     CH.sub.3                                                                             methanol      -30°                                                                             110     50                                     ______________________________________                                         THF = tetrahydrofuran                                                         EtOAc = ethyl acetate                                                    

EXAMPLE 3

The method of Example 2 was repeated with comparable results employingeach of the following co-solvents:

ethanol

n-propanol

iso-butanol

n-butanol

t-butanol

dioxane

ethyl ether

isopropyl ether

dimethoxy ethane

2-methoxy ethanol

2-ethoxy ethanol

ethylene glycol

EXAMPLE 4

In a 3-neck round bottom flask equipped with a stirring bar, a gas inlettube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml ofwater and sodium bromide (0.20 mole). The solution was cooled to atemperature of 0° to 20° C. The addition funnel was charged with asolution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuranand this was added dropwise to the rapidly stirred reaction flask whilegaseous chlorine (0.40 mole) is added via the gaseous inlet tube. Therate of the alcohol addition was such that a yellow orange color wasmaintained. The reaction temperature was kept below 20° C. with ice bathcooling. After the alcohol and chlorine had both been added to thereaction flask, the temperature was raised to reflux to distill off thetetrahydrofuran. The isolation procedure of Example 1 was used toisolate 12.47 g of pure maltol (55% yield).

Substantially the same results are obtained substituting potassiumbromide for sodium bromide.

EXAMPLE 5

The method of Example 4 was repeated under varying conditions shown inTable 2 with furfuryl alcohols of the formula ##STR8##

                  Table 2                                                         ______________________________________                                        One Pot Process using Cl-Br as the oxidant, generated by                      addition of chlorine in situ to NaBr.                                                              Temp.     Temp.                                                               (° C) of                                                                         (° C) of                                                                       Yield                                  R      Cosolvent     oxidation hydrolysis                                                                            (%)                                    ______________________________________                                        CH.sub.3                                                                             THF            20°                                                                             104     55                                     CH.sub.3                                                                             THF            27°                                                                             110     54                                     CH.sub.3                                                                             THF            15°                                                                             110     52                                     CH.sub.3                                                                             Isopropyl ether                                                                              25       110     46                                     CH.sub.3                                                                             ethyl ether    20       110     43                                     CH.sub.3                                                                             acetone        15       105     47                                     CH.sub.3                                                                             CH.sub.3 OH    15       110     32                                     CH.sub.2 CH.sub.3                                                                    THF            16       113     47                                     H      THF            20       109     48                                     ______________________________________                                         THF = tetrahydrofuran                                                    

EXAMPLE 6

In a 3-neck round bottom flask equipped with a magnetic stirring bar, agas inlet tube, a thermometer and an addition funnel was added 50 ml oftetrahydrofuran and 50 ml of water. This solution was then cooled to 0°C. and chlorine (0.10 mole) was added slowly to the reaction flask while1(2-furyl)-1-ethanol (0.09 mole) was added dropwise. The temperature ofthe reaction mixture was not allowed to exceed 10° C. Bromine (0.10mole) was then added and the reaction mixture heated to reflux.Following the isolation procedure of Example 1, a yield of 5.7 g ofmaltol was obtained.

EXAMPLE 7

To a 4-neck round bottom flask equipped with a thermometer, a condensorand two addition funnels was charged 50 ml of tetrahydrofuran and 50 mlof water and the solution was cooled to 10° C. To this well stirredsolution was added together in the two addition funnels bromine (0.20mole) and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of thereaction was maintained at 15° C. throughout the double addition. Thereaction mixture was then heated to 75° C. for 10 hours. Maltol wasisolated by the procedure of Example 1 (53% yield).

EXAMPLE 8

The method of Example 7 was repeated under varying conditions shown inTable 3 with furfuryl alcohols of the formula ##STR9##

                  Table 3                                                         ______________________________________                                                          Temp.        Temp.                                                            (° C) of                                                                            (° C of                                                                        Yield                                  R      Cosolvent  oxidation    hydrolysis                                                                            (%)                                    ______________________________________                                        CH.sub.3                                                                             THF         15°  75     53                                      CH.sub.3                                                                             CH.sub.3 OH  5° 105     47                                      CH.sub.3                                                                             none        15° 100     30                                      CH.sub.2 CH.sub.3                                                                    THF         25         105     47                                      H      THF         15° 100     45                                      CH.sub.3                                                                             THF         50° 100     20                                      ______________________________________                                    

EXAMPLE 9

A 2.8 M sodium hypochlorite solution was prepared by passing chlorinegas (42.6 g) into a solution of 48 g of sodium hydroxide in 150 ml ofwater at 0° C. A solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 mlof tetrahydrofuran and 15 ml of water was prepared in a 3-neck flask andcooled to 5° C. While maintaining a pH from 1.0 to 0.8 with 6 N HCl,21.7 ml of the hypochlorite solution was added dropwise to the reactionflask over a period of about 33 minutes while maintaining the reactiontemperature below 5° C. A 15 ml portion of concentrated HCl was thenadded to the reaction mixture which was then heated to remove thetetrahydrofuran by distillation. Heating was continued for an additionalhour. Maltol ws isolated as described in Example 1.

Substantially the same results are obtained when sodium hypobromite isused in placed of sodiumm hypochlorite.

EXAMPLE 10

To a solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml oftetrahydrofuran and 15 ml of water at 5° C. is added 21.7 ml of 2.8 Msodium hypochlorite solution. Chlorine (0.05 mole) is added to thereaction flask via a gas inlet tube maintaining the reaction temperaturebelow 5° C. The reaction mixture is then heated to reflux and thetetrahydrofuran removed by distillation. Heating is continued for anadditional hour. The reaction mixture is cooled and maltol is isolatedby the procedure described in Example 1.

EXAMPLE 11

To a 3-neck round bottom flask is charged a solution of 50 ml of waterand 20 ml of tetrahydrofuran and the solution is cooled to 0° C. Anaddition funnel is charged with a solution of 1(2 furyl)-1-ethanol (0.89mole) in 25 ml of tetrahydrofuran and this solution is added dropwise tothe reaction flask while BrCl (0.30 mole) is added via a gas inlet tube.The rate of addition is such that all the furfuryl alcohol is added inthe first 1.3-1.5 equivalents of BrCl while maintaining the temperaturebelow 30° C. The reaction mixture is heated to reflux and thetetrahydrofuran removed by distillation. When the temperature reaches105° C., a condensor is attached and the reaction mixture heated underreflux for about 2 hous. The reaction mixture is cooled and maltolisolated by the method of Example 1.

EXAMPLE 12

In a 3-neck round bottom flask equipped with a magnetic bar, athermometer and two addition funnels is charged 25 ml of tetrhydrofuranand 50 ml of water. To this solution is added 1(2-furfyl)-1-ethanol(0.89 mole) in 25 ml of tetrahydrofuran while bromine (0.16 mole) isadded dropwise while maintaining the temperature below 15° C. After theadditions are complete, chlorine (0.10 mole) is added via a gas inlettube and the reaction is heated to reflux. Maltol is isolated from thecooled solution by the method of Example 1.

EXAMPLE 13 6-hydroxy-2-methyl-2H-pyran-3(6H)-one

To a solution of 25 g of 1(2-furfyl)-1-ethanol in 125 ml oftetrahydrofuran and 125 ml of water at 5° C. was added 1 equivalent ofbromine. The temperature was maintained at 5°-10° C. throughout theaddition. The solution was adjusted to pH 2.1 and extracted with ethylacetate (3 × 50 ml). The ethyl acetate extract was dried and evaporatedto give a yellow oil. The oil was chromatographed on silica gel andeluted with chloroform-ethyl acetate (3:1) to give 4.8 g of clear oilwhich was shown by spectral data to be identical with6-hydroxy-2-methyl-2H-pyran-3(6H)-one prepared from 6-methoxy-2-methyl-2H-pyran-3(6H)-one by acid hydrolysis [Tetrahedron 27, 1973 (1971)].

IR (CHCl₃) 3700, 3300, 1700 cm⁻¹.

NMR (CDCl₃, δ): 6.8-7.1 (1H, d of d); 6.0-6.2 (1H, d), 5.6 (1H, br. s,exchanges with D₂ O); 5.4- 5.5 (1H, d); 4.8-5.0 (1H, q); 1.3-1.6 (3H,t).

EXAMPLE 14

The method of Example 13 was repeated with a furfuryl alcohol of theformula ##STR10## to yield a compound of the formula ##STR11## wherein Ris hydrogen or ethyl.

Ethyl compound: IR (CHCl₃) 3600, 3340, 1706 cm⁻¹.

Hydrogen compound: IR (CHCl₃) 3565, 3300, 1703 cm⁻¹.

EXAMPLE 15 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one

To a solution of 25 g of 1(2-furyl)-1-ethanol in 125 ml oftetrahydrofuran and 125 ml of water at 0°-5° C. was added dropwise 2.2equivalents of bromine. Throughout the addition the temperature wasmaintained at 5°-10° C. After the bromine addition the solution wasstirred at room temperature for 30 minutes and the pH adjusted to 2.1with 2 N NaOH solution. The reaction mixture was extracted with ethylacetate (3 × 100 ml). The ethyl acetate extracts were combined, driedover MgSO₄, filtered and taken to dryness. The residue waschromatographed on silica gel and eluted with chloroform-ethyl acetate(95:5). The product was an orange oil which was rechromatographed onsilica gel and eluted with chloroform-ethyl acetate (95:5).

NMR (CDCl₃, δ) 7.3 (1H, d); 5.6 (1H, d); 4.7-5.0 (1H, q); 1.1-1.5 (3H,m).

EXAMPLE 16

The method of Example 15 was repeated with a furfuryl alcohol of theformula ##STR12## to yield a compound of the formula ##STR13## wherein Ris hydrogen or ethyl.

Ethyl compound 4-bromo-6-hydroxy-2 ethyl 2H-pyran-3(6H)-one NMR (CDCl₃,δ) 7.4 (1H, d); 5.8 (1H, d); 4.6-4.9 (1H, m); 1.8-2.2 (2H, m); 1.0-1.3(3H, t).

Hydrogen compound 4-bromo-6-hydroxy-2H-pyran-3(6H)-one NMR (CDCl₃, δ)7.4 (1H, d); 5.5 (1H, d); 4.6 (2H, d of d).

EXAMPLE 17

A solution of 4-bromo-6-hydroxy-2-methyl-2-methyl-2H-pyran-3(6H)-one wasprepared by dissolving the compound in either aqueous inorganic ororganic acids. The solution was then heated to reflux, cooled to roomtemperature, the pH adjusted to 2.1 with 6 N NaOH and the reactionmixture extracted with chloroform. Concentration yielded maltol. Theacids, time of reaction and yields of maltol were as follows:

    ______________________________________                                                                Reaction    Yield                                     Acid     Concentration(%)                                                                             Time (Hrs.) (%)                                       ______________________________________                                        HCl      32             2           68                                        HCl      32             5           52                                        HCl      18             5           35                                        HCl      25             3           49                                        HBr      18             5           24                                        H.sub.2 SO.sub.4                                                                       35             2           26                                        H.sub.3 PO.sub.4                                                                       35             2           29                                        CH.sub.3 COOH                                                                          35             2           69                                        CF.sub.3 COOH                                                                          neat           3           36                                        HNO.sub.3                                                                              35             3           0.4                                       CF.sub.3 COOH                                                                          neat           3           70                                        CH.sub.3 COOH                                                                          neat           3           77                                        HCOOH    neat           3           24                                        H.sub.2 SO.sub.4                                                                       35             5           48                                        ______________________________________                                    

In addition, organic solvents such as benzene and toluene, together withacidic materials such as p-toluenesulfonic acid and Amberlite IR-120,may also be used.

EXAMPLE 18

The method of Example 15 was repeated employing chlorine in place ofbromine and the appropriate furfuryl alcohols to produce the followingcompounds:

Methyl: 4-chloro-6-hydroxy-2-methyl-2H-pyran-3(6H)-one NMR (CDCl₃, δ):7.1 (1H, d); 5.8 (1H, d); 4.6-5.0 (1H, m); 4.4 (1H, br. s); 1.2-1.5 (3H,m).

Ethyl 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3(6H)-one NMR (CDCl₃, δ):7.0-7.1 (1H, d); 5.6-6.0 (2H, m), 4.4-5.0 (1H, m); 1.6-2.1 (2H, m);0.9-1.1 (3H, t).

Hydrogen: 4-chloro-6-hydroxy-2H-pyran-3(6H)-one NMR (CDCl₃, δ): 7.1-7.2(1H, d); 5.6 (1H, d); 4.4-4.9 (2H, d of d) (D₂ O added).

EXAMPLE 19

The method of Example 15 may be repeated to yield a compound of theformula ##STR14## where R is propyl, butyl, phenyl or benzyl; X isbromine or chlorine.

EXAMPLE 20

4-Bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one was heated under vacuumfor 16 hours at 40° C. The resulting oily solid was crystallized fromisopropyl alcohol to yield 6,6'-oxybis[4-bromo-2-methyl-2H-pyran-3(6H)-one], mp 125° C.

EXAMPLE 21

The method of Example 20 may be repeated starting with a compound of theformula ##STR15## to yield a compound of the formula ##STR16## wherein Ris hydrogen, ethyl, propyl, butyl, phenyl or benzyl; X is bromine orchlorine.

    ______________________________________                                        R           X              M.P. (° C.)                                 ______________________________________                                        CH.sub.3    Cl             177-179                                            CH.sub.2 CH.sub.3                                                                         Cl             132-135                                            ______________________________________                                    

EXAMPLE 22

A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one (0.0025mole) in 20 ml of 35% phosphoric acid was refluxed for about 5 hours.Maltol (34%) was isolated by the method of Example 1.

EXAMPLE 23

A compound of the formula ##STR17## wherein R is hydrogen, methyl,ethyl, propyl, butyl, phenyl or benzyl and X is bromine or chlorine istreated by the method of Example 22 to yield of a compound of theformula ##STR18## wherein R is as defined above.

EXAMPLE 24

A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mole) in 20 mlof acetic acid as treated with gaseous chlorine (0.01 mole) at roomtemperature. The reaction mixture was then heated to reflux for aboutone hour, cooled to room temperature, diluted with 20 ml of water, thepH adjusted with 50% NaOH solution to 7.0 and the reaction mixtureextracted with chloroform. The chloroform extract was concentrated toyield maltol which was recrystallized from methanol to give pure product(56%), mp 159.5°-160.5° C.

EXAMPLE 25

The method of Example 24 may be repeated starting with a compound of theformula ##STR19## wherein R is hydrogen, alkyl of 2 to 4 carbon atoms,phenyl and benzyl; R' is alkyl of 2 to 4 carbon atoms and ##STR20##where R" is methyl, ethyl or phenyl to yield a gamma-pyrone of theformula ##STR21## wherein R is hydrogen, alkyl of 2 to 4 carbon atoms,phenyl or benzyl.

EXAMPLE 26

The method of Example 24 may be repeated with comparable resultsreplacing acetic acid with each of the following solvents:

formic acid

methanol

ethanol

tetrahydrofuran

benzene

ethylene glycol

trifluoroacetic acid

acetone

acetonitrile

EXAMPLE 27

The method of Example 24 may be repeated with comparable resultsreplacing chlorine with bromine, sodium or potassium hypochlorite orhypobromite, gaseous bromine chloride or bromine chloride prepared insitu by the addition of chlorine to a solution containing sodium bromideor bromine to a solution of sodium chloride.

EXAMPLE 28 4-chloro-6-methoxy-2-methyl-2H-pyran-3(6H)-one

To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.05 mole) in 70ml of dichloromethane at - 10° C. was added chlorine (0.05 mole) via agas inlet tube. Following this addition, triethylamine (0.05 mole) wasadded slowly maintaining the temperature at - 10° C. After 30 minutes ofstirring the reaction mixture was allowed to warm to room temperature,filtered to remove triethylamine hydrochloride and the solvent removedunder vacuum. Redissolving the crude product in ether-benzene andfiltration removed the last traces of triethylamine hydrochloride.Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-3(6H)-one(yield, 99%). NMR analysis of the signals at 5.05 to 5.25 clearly showedtwo doublets in a 3 to 1 ratio corresponding to the proton at C-6 of thetwo possible isomers of the compound. Both optical forms of the transisomer had been synthesized from a carbohydrate precursor by Paulsen,Eberstein and Koebernick, Tetrahedron Letters 4377 (1974).

EXAMPLE 29 4-bromo-6-methoxy-2-methyl-2H-pyran-3(6H)-one

The method of Example 28 was repeated replacing chlorine with bromine toobtain 4-bromo-6-methoxy-2-methyl-2H-pyran-3(6H)-one in 93% yield. Thetwo optical forms of the trans isomer had been synthesized by Paulsenand co-workers, Tetrahedron Letters 4377 (1974).

EXAMPLE 30

The methods of Examples 28 and 29 may be repeated starting with acompound of the formula: ##STR22## wherein R is hydrogen, alkyl of 2 to4 carbon atoms, phenyl or benzyl R' is alkyl of 2 to 4 carbon atoms toyield a compound of the formula ##STR23## wherein R and R' are asdefined above; and X is chlorine or bromine.

EXAMPLE 31 4-bromo-6-acetyl-2H-pyran-3(6H)-one

A solution in dichloromethane of 6-acetyl-2H-pyran-3(6H)-one, preparedby the method described in Tetrahedron 27, 1973 (1971), was brominatedby the method of Example 6 to yield 4-bromo-6-acetyl-2H-pyran-3(6H)-one,mp 78°-80° C. The mass spectrum of the compound showed the expectedparent peaks at 234 and 236 mass units.

EXAMPLE 32 4-bromo-6- acetyl-2-methyl-2H-3(6H)-one

The method of Example 31 was repeated with 6-acetyl-2-methyl-2H-pyran-3(6H)-one to yield4-bromo-6-acetyl-2-methyl-2H-3(6H)-one which showed parent masses of249.96 and 247.96 by mass spectroscopy and the following MNR spectrum:(δ, CDCl₃):7.3(1H,d); 6.4(1H,d of d); 4.7(1H,Q); 2.2(3H,S); 1.4(3H,S).

EXAMPLE 33

The method of Example 28 may be repeated employing chlorine in place ofbromine starting with a compound of the formula ##STR24## wherein R ishydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' is alkyl of1 to 4 carbon atoms and ##STR25## where R' is methyl, ethyl or phenyl toyield a compound of the formula ##STR26## wherein R and R' are asdefined above and X is chlorine.

EXAMPLE 34

To a round bottom flask equipped with a stirring bar and a condenser wasadded 4-chloro-6-methoxy-2-methyl-2H-pyran-3(6H)-one and acetic acid andthe reaction mixture heated to reflux for an hour. Maltol (65%) wasobtained on cooling.

EXAMPLE 35

The method of Example 34 was repeated with comparable results addingformic acid in place of acetic acid.

EXAMPLE 36

The method of Example 34 may be repeated starting with a compound of theformula ##STR27## wherein R is hydrogen, alkyl of 1 to 4 carbon atoms,phenyl or benzyl; R' is alkyl of 1 to 4 carbon atoms and ##STR28## whereR" is methyl, ethyl or phenyl; X is bromine or chlorine to yield acompound of the formula ##STR29## where R is hydrogen, alkyl of 1 to 4carbon atoms phenyl or benzyl.

EXAMPLE 37 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one

In a three necked round bottom flask were combined 28 ml of methanol and38 ml of water. The solution was cooled to -15° C. and 0.166 mole of5-methyl2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1973, 1960) and0.416 mole of chlorine were added simultaneously. During the addition,the reaction was maintained between -16° and -8° C. When addition wascompleted, the solution was warmed to 80° C. and refluxed for about 3hours. Upon cooling to room temperature, the pH was adjusted to 2.1 andextracted with chloroform (3 × 100 ml). The combined organic layers werewashed with water, brine and dried over magnesium sulfate. The organicsolution was filtered and evaporated to give a thick dark solid. Thesolid was recrystallized twice from methanol to give 8.06 grams (30%yield) of white solid. Sublimation yielded pure product, m.p. 157°-159°C.

Analysis: Calc'd. for C₈ H₁₀ O₃ : C, 62.33; H, 6.54. Found : C, 62.05;H, 6.44.

NMR (CDCl₃ δ); 6-CH₃, 2.33 (3H, s); 2-CH₃, 1.30 (3H, t); 2-CH₂ -, 2.75(2H, quartet); 5H, 6.23 (1H, s).

EXAMPLE 38 2,6-dimethyl-3-hydroxy-4H-pyran-4-one

In a three necked round bottom flask were combined 28 ml of water and 32ml of methanol and cooled to -15° C. The solution was treated with 0.167mole of 5-methyl-2-(α-hydroxy-ethyl)furan (J. Org. Chem., 26, 1673,1960) and 0.416 mole of chlorine simultaneously. The temperature wasmaintained at -15° to -10° C. during addition. The reaction was allowedto warm to room temperature over 30 minutes and heated to reflux for 3hours. The cooled solution was adjusted to pH 2.1 and extracted withchloroform (3 × 100 ml). The chloroform extracts were combined, washedwith water and brine, dried over magnesium sulfate, filtered andevaporated. The residue, a dark oil, was chromatographed on silica geldeveloped with methylene chloride/ethyl acetate (95:5). The product,isolated by evaporation, was recrystallized from methanol as a tan solid(yield, 25%). Sublimation yielded white crystals, m.p. 161°-163° C.

Analysis: Calc'd. for C₇ H₈ O₂ : C, 59.99; H, 5.75. Found : C, 59.83; H,5.82.

NMR (CDCl₃, δ); 6-CH₃, 2.33 (3H, s); 2-CH₃, 2.26 (3H, s); 5-H, 6.10 (1H,s).

What is claimed is:
 1. A process for preparing a gamma-pyrone of theformula ##STR30## which comprises contacting a furfuryl alcohol of theformula ##STR31## wherein R is hydrogen, alkyl of 1 to 4 carbon atoms,phenyl or benzyl and R'" is hydrogen or alkyl of 1 to 4 carbon atoms inaqueous solution at a temperature of -50° to 50° C with at least twoequivalents of a halogen oxidant selected from the group consisting ofchlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acidor mixtures thereof and heating the formed 4-halo-dihydropyran untilhydrolysis is substantially complete.
 2. The process of claim 1 whereinthe hydrolytic reaction temperature is 70° to 160° C.
 3. The process ofclaim 1 wherein a co-solvent is present and said cosolvent is selectedfrom the group consisting of alkanols or diols of 1 to 4 carbon atoms,ethers of 2 to 10 carbon atoms, low molecular weight ketones, nitriles,esters and amides.
 4. The process of claim 3 wherein said alkanol ismethanol
 5. The process of claim 3 wherein said ether istetrahydrofuran.
 6. The process of claim 3 wherein said ether isisopropyl ether.
 7. The process of claim 3 wherein said ketone isacetone.
 8. The process of claim 1 wherein said halogen oxidant ischlorine.
 9. The process of claim 1 wherein said halogen oxidant isbromine-chloride.
 10. The process of claim 1 wherein said gamma-pyroneis 2-methyl-3-hydroxy-4H-pyran-4-one.
 11. The process of claim 1 whereinsaid gamma-pyrone is 2-ethyl-3-hydroxy-4H-pyran-4-one.
 12. The processof claim 1 wherein said gamma-pyrone is6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one.
 13. A process for preparing acompound of the formula ##STR32## wherein R is hydrogen, alkyl of 1 to 4carbon atoms, phenyl or benzyl; R'" is hydrogen or alkyl of 1 to 4carbon atoms; and X is chlorine or bromine which comprises contacting acompound of the formula ##STR33## in water or water and organic solventat a temperature of -50° to 50° C with at least two equivalents of ahalogen oxidant selected from the group consisting of chlorine, bromine,bromine chloride, hypochlorous acid, hypobromous acid or mixturesthereof until the reaction is substantially complete.
 14. A process forpreparing a gamma-pyrone of the formula ##STR34## which comprisesheating in aqueous solution until hydrolysis is substantially complete acompound of the formula ##STR35## wherein R is hydrogen, alkyl of 1 to 4carbon atoms, phenyl or benzyl; R' is hydrogen, alkyl of 1 to 4 carbonatoms or ##STR36## wherein R" is methyl, ethyl or phenyl; R"' ishydrogen or alkyl of 1 to 4 carbon atoms; and X is chlorine or bromine.